Project Summary/Abstract: Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. Even when drugs are approved there is a growing concern that cancer chemotherapeutics result in cardiotoxicity via unknown mechanisms, making it difficult to predict which patients will be affected. The discovery of human induced pluripotent stem (hiPS) cells has enabled the tissue engineering community to develop in vitro human models of tissues and organs to be used for high content drug screening and patient specific medicine. We envisage the device and stem cell combinations proposed in this application will result in an in vitro microphysiological system (MPS) that significantly reduces the cost of bringing a new drug candidate to market while improving efficacy. Specifically, a physiologically functioning iPS-derived in vitro model of cardiac tissue (e.g., MPS) would be a significant advancement for understanding cardiotoxicity (e.g., with chemotherapy), studying disease mechanisms, and developing new strategies to treat cardiac diseases. As a basis for proof-of-principle of our methodology and workflow, we have chosen to focus on illustrative forms of the most common cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The principal goal of this proposal is to establish an in vitro human cardiac MPS model based on geometric models of human ventricular myocardium with populations of normal, genetically engineered, and disease specific hiPS cells differentiated into cardiac myocytes (hiPS-CMs). We plan to assess in HCM and DCM lines the toxicity of chemotherapeutic compounds that are currently on the market, FDA approved, and are known to cause mild or reversible cardiac toxicity in some populations. A key strength of this proposal is that once we have calibrated our MPS with isogenic hiPS-CMs, then we will proceed to testing hiPS-CMs from cardiomyopathy patients with diverse backgrounds, as a step to using our MPS to advance the goals of personalized medicine. This comparison is critical, as patient-derived iPS lines that have different genetic backgrounds have unknown effects on physiology, so it is difficult to know if an altered response in our cardiac MPS is due to the disease, or normal variation. We have proposed three specific aims to achieve our goals. If we are successful in completing our Specific Aims, then our human in vitro MPS of cardiac tissue could be a powerful tool for screening chemotherapeutic drug candidates for treatment, and reduce both the time and cost of the drug discovery cycle.